Kiełbowski Kajetan, Żychowska Justyna, Becht Rafał
Department of Clinical Oncology, Chemotherapy and Cancer Immunotherapy, Pomeranian Medical University, Szczecin, Poland.
Front Pharmacol. 2023 Oct 25;14:1285374. doi: 10.3389/fphar.2023.1285374. eCollection 2023.
Fusions and mutations of anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor, have been identified in several neoplastic diseases. Rearranged ALK is a driver of tumorigenesis, which activates various signaling pathway associated with proliferation and survival. To date, several agents that target and inhibit ALK have been developed. The most studied ALK-positive disease is non-small cell lung cancer, and three generations of ALK tyrosine kinase inhibitors (TKIs) have been approved for the treatment of metastatic disease. Nevertheless, the use of ALK-TKIs is associated with acquired resistance (resistance mutations, bypass signaling), which leads to disease progression and may require a substitution or introduction of other treatment agents. Understanding of the complex nature and network of resistance mutations may allow to introduce sequential and targeted therapies. In this review, we aim to summarize the efficacy and safety profile of ALK inhibitors, describe off-target anticancer effects, and discuss resistance mechanisms in the context of personalized oncology.
间变性淋巴瘤激酶（ALK）作为一种酪氨酸激酶受体，其融合和突变已在多种肿瘤性疾病中被发现。重排的ALK是肿瘤发生的驱动因素，可激活与增殖和存活相关的各种信号通路。迄今为止，已开发出几种靶向并抑制ALK的药物。研究最多的ALK阳性疾病是非小细胞肺癌，三代ALK酪氨酸激酶抑制剂（TKIs）已被批准用于治疗转移性疾病。然而，ALK-TKIs的使用与获得性耐药（耐药突变、旁路信号传导）相关，这会导致疾病进展，可能需要更换或引入其他治疗药物。了解耐药突变的复杂性质和网络可能有助于引入序贯和靶向治疗。在本综述中，我们旨在总结ALK抑制剂的疗效和安全性，描述脱靶抗癌作用，并在个性化肿瘤学背景下讨论耐药机制。
